Radioactive intraluminal endovascular prosthesis and method for the treatment of aneurysms

ABSTRACT

A method for increasing the rate of thrombus formation and/or proliferative cell growth of a selected region ( 21 ) of cellular tissue ( 22 ) including the step of endovascularly irradiating the selected region ( 21 ) with radiation, having a dose range of endovascular radiation of about 1 Gy to about 600 Gy at a low dose rate of about 1 cGy/hr to about 320 cGy/hr, to increase thrombus formation and/or cell proliferation of the affected selected region ( 21 ). Preferably, the delivery means includes a deformable endovascular prosthesis ( 25 ) adapted for secured positioning adjacent to the selected region ( 21 ) of cellular tissue ( 22 ), and a radioactive source. This source cooperates with the deformable endovascular device ( 25 ) in a manner endovascularly irradiating the selected region with radiation, having the above-indicated dose range and low dose rate of endovascular radiation to increase thrombus formation and/or cell proliferation of the affected selected region ( 21 ).

TECHNICAL FIELD

[0001] The present invention relates, generally, to the treatment ofvascular disorders and, more particularly, to the treatment of aneurysmswith radioactive intraluminal endovascular prosthesis.

BACKGROUND ART

[0002] While conventional bypass graft treatment of aneurysms hassteadily improved, mortality rates continue to be relatively high incases such as abdominal aortic aneurysms. These often asymptomaticaneurysms 15 of blood vessel 16, as shown in FIG. 1, generallyprogressively enlarge in most patients over time, increasing the risk ofrupture. Traditional bypass grafts are then required which are extremelyinvasive and include all the risks of open surgeries such as paraplegia,renal insufficiency, and myocardial infarction. Moreover, even three (3)to five (5) years after these surgeries, complications may arise whichinclude concomitant coronary atherosclerotic disease, graft infection,aortoenteric fistula, thromboembolish, and anastomotic aneurysms.

[0003] In the recent past, more innovative approaches have evolved forthe treatment of aneurysms. For example, DACRON® grafts, endovascularstent grafts and covered stents (referred heretofore generally as “stentgrafts”), which have rapidly developed in an effort to expand stenttechnology, may be employed as a means of aneurysm treatment. Thesehybrid devices combine graft material with a stent or stent-like deviceto provide an expandable, stent-like structure having an imperviousluminal surface.

[0004] These combination of features, once implanted, are very conduciveto achieve endovascular exclusion of aneurysms. Typically, a graftmaterial is mounted to and positioned along an exterior circumferentialsurface and/or the interior circumferential surface of the prosthesis ina manner forming an endovascular, blood impervious lumen therethrough. Aproximal end of the graft is preferably endovascularly positioned justupstream from the vascular disorder while a distal end thereofterminates at a position just downstream thereof. As the proximal endand the distal end of the stent graft become anastomosed with the vesselwall, the vascular disorder becomes endovascularly excluded from theblood flow while the is stent graft impervious lumen maintains vesselpatency

[0005] Upon proper endovascular deployment and seal formation of thestent, cell matrix formation and tissue healing may commence in theaneurysmal sac and on the luminal surface. For example, in theaneurysmal sac between stent graft and the vascular wall, the residualblood clotting and inflammatory response cause cellular proliferationand connective formation, forming a matrix that may seal the sac. Inaddition to the sealing, the resulted wall, which is a combination ofprosthesis, connective tissue matrix, and arterial wall provides aconduit support of proper hemodynamic blood flow.

[0006] Intraluminally, thromboembolic processes will occur on theluminal surface of the graft/stent. Briefly, during this thromboticphase, platelets and blood clots adhere to the surface to form a fibrinrich thrombus. Endothelial cells then appear, followed by intensecellular infiltration. Finally, during the proliferative phase,actin-positive cells colonize the residual thrombus, resorbing thethrombus.

[0007] The primary problem associated with this technique is the timeperiod required for endovascular sealing and repair of the aneurysmalsac. Tissue response to injuries of this nature are generally on theorder of a few months to years. This is especially true for the luminalsurface of the graft material where organized thrombus formation may bedifficult to achieve. Such endothelial cell growth to line the lumen ofthe stent graft may require years of healing or may never be fullycompleted.

[0008] Accordingly, several clinical complications may result due toimproper delayed cellular healing. One of the most prevalent problems,aortoentenic fistula, arises when the seal integrity between the vesselwall and the proximal end of the stent graft is compromised due to slowthrombus formation and incomplete tissue growth. Such upstream, proximalseal breaches cause blood infiltration through the incompleteanastomosis that may lead to abdominal blood loss. Stent graftsefficiency and effectiveness are substantially reduced since the luminalsurface is not re-endothelialized, exposing the foreign surface to therisk of thrombosis and its complications.

[0009] There is a need, therefore, to increase the effectiveness andefficiency of the stent graft to reduce the time period for vascularrepair.

DISCLOSURE OF INVENTION

[0010] Accordingly, a method is provided for promoting and increasingthe rate of at least one of thrombus formation and proliferative cellgrowth of a selected region of cellular tissue. The method includes thestep of endovascularly irradiating of the selected region endovascularradiation, having a dose range of about 1 Gy to about 600 Gy at a lowdose rate of about 1 cGy/hr to about 320 cGy/hr, to promote thrombusproliferation followed by cellular proliferation of the affectedselected region. Preferably, the dose of endovascular radiation is about1 Gy to about 25 Gy at the graft surface, and at a low dose rate ofabout 1 cGy/hr to about 15 cGy/h. The selected region is preferably theluminal blood contents such as platelets, clotting proteins, and fibrin,while the target cells may include circulatory stem cells and cells fromthe adjacent connective tissue.

[0011] In one embodiment, the present method includes the step ofpositioning a deformable endovascular device, adapted to endovascularlyemit the radioactive field, proximate the aneurysm. This step isperformed by implanting the deformable endovascular device adjacent theaneurysm of the blood vessel. To generate the radioactive field andbefore the positioning step, the present invention includes the step ofembedding radioactive material in the deformable endovascular device.

[0012] In another embodiment the embedding step further includes thestep of: embedding a central portion of the endovascular prosthesis,sized to extend substantially adjacent the aneurysm when properlypositioned, with a first radioactive activity generating the first namedradiation acting upon the aneurysm; and embedding the end portions ofthe endovascular prosthesis, positioned on opposed sides of the centralportion and extending beyond the upstream end and the downstream end ofthe aneurysm, with a second radioactive activity generating a secondradiation having a dosage adapted to decrease thrombus formation and/orcell proliferation of the affected regions flanking the aneurysm.

[0013] In still another embodiment, the method of the present inventionincludes the step of positioning an intra-luminal endovascularprosthesis in the vessel proximate the aneurysm; and deploying theendovascular prosthesis from a contracted condition to an expandedcondition, wherein the endovascular prosthesis engages the interiorwalls of the blood vessel forming a void between the endovascularprosthesis and the aneurysm for receipt of the radioactive seeds thereinand such that the radioactive seeds are substantially retained is thevoid by the endovascular prosthesis. In another method, radiosensitizersmay be deposited within the void or the aneurysmal sac, or be insertedinto the aneurysmal contents. These radiosensitizers will be maderadioactive or activated through external beam radiation or endovascularirradiation.

[0014] In another aspect of the present invention, a proliferationdevice is provided for increasing the rate of proliferative cell growthand/or induce thrombus formation of a selected region of cellulartissue. The proliferation device includes a deformable endovasculardevice adapted for secured positioning adjacent to the selected regionof cellular tissue, and a radioactive source. This source cooperateswith the deformable endovascular device in a manner endovascularlyirradiating the selected region with endovascular radiation, having adose range of about 1 Gy to about 600 Gy at a low dose rate of about 1cGy/hr to about 320 cGy/hr, to increase thrombus formation and/or cellproliferation of the affected selected region.

[0015] The radioactive source is provided by radioactive materialembedded in the deformable endovascular device. In one embodiment, thedeformable endovascular device is provided by radioactive coils,endovascularly irradiating the radiation, sized and dimensioned forreceipt in a pseudoaneurysm. In another embodiment, for saccular orfusiform aneurysms, the deformable endovascular device is provided by atubular-shaped intraluminal endovascular prosthesis radially expandablefrom a contracted condition and an expanded condition. In the contractedcondition, percutaneous delivery into the blood vessel is enabled, andan expanded condition, the deformable endovascular device radiallycontacts the interior walls of the blood vessel for implanting thereto.In another method, the described endovascular sources can beradiosensitizers or radioactive sources that are coated with biologicfactors such as growth factors, adhesion molecules, and organic matrix

[0016] The thrombus formation and/or cellular proliferation devicefurther includes a tubular-shaped sheath device defining a lumentherethrough, and cooperating with the endovascular prosthesis tosubstantially prevent fluid communication between fluid flow through thelumen of the blood vessel and the aneurysm, while maintaining vesselpatency. For the aneurysms, the prosthesis is sized and dimensioned toextend beyond an upstream end of the aneurysm and beyond a downstreamend of the aneurysm each by at least about 1.0 mm when properlypositioned in the vessel.

BRIEF DESCRIPTION OF THE DRAWING

[0017] The assembly of the present invention has other objects andfeatures of advantage which will be more readily apparent from thefollowing description of the best mode of carrying out the invention andthe appended claims, when taken in conjunction with the accompanyingdrawing, in which:

[0018]FIG. 1 is a fragmentary, side elevation view, in cross-section, ofa typical fusiform aneurysm.

[0019]FIG. 2 is a fragmentary top perspective view, partially brokenaway, of an aneurysm incorporating a radioactive stent graft deviceconstructed in accordance with the present invention.

[0020]FIG. 3 is a fragmentary, side elevation view, in cross-section, ofthe stent graft device of FIG. 2 being percutaneously delivered in acontracted condition.

[0021]FIGS. 4A and 4B is a sequence of side elevation views, incross-section, of the stent graft device of FIG. 3 being moved from thecontracted condition to an expanded condition.

[0022]FIG. 5 is an enlarged 2-dimensional representation of amulti-cell, pre-deployed stent applicable for use with the presentinvention.

[0023]FIG. 6 is a 2-dimensional dose graphical representation for aPhosphorus 32 stent taken substantially along the plane of the line 6-6in FIG. 5.

[0024]FIG. 7 is an enlarged, fragmentary, side elevation view, incross-section, of the expanded stent graft device of FIG. 4B, andillustrating delivery of the endovascular radiation from the radioactivestent.

[0025]FIG. 8 is a fragmentary, side elevation view, in cross-section, ofthe stent graft device and repaired aneurysm of FIG. 4B in a stableproliferative phase.

[0026]FIG. 9 is an enlarged, front elevation view, in cross-section, ofthe of the deployed stent graft device taken substantially along theplane of the line 9-9 in FIG. 8.

[0027]FIG. 10 is a fragmentary, side elevation view, in cross-section,of an alternative embodiment stent graft device of FIG. 4B having anexternal graft.

[0028]FIG. 11 is a fragmentary, side elevation view, in cross-section,of an alternative embodiment stent graft device of FIG. 4B incorporatingthe deposition of radioactive seeds.

[0029]FIGS. 12A and 12B is a sequence of side elevation views, incross-section, of a pseudoaneurysm having a radioactive coil device ofthe present invention deployed therein.

BEST MODE OF CARRYING OUT THE INVENTION

[0030] While the present invention will be described with reference to afew specific embodiments, the description is illustrative of theinvention and is not to be construed as limiting the invention. Variousmodifications to the present invention can be made to the preferredembodiments by those skilled in the art without departing from the truespirit and scope of the invention as defined by the appended claims. Itwill be noted here that for a better understanding, like components aredesignated by like reference numerals throughout the various figures.

[0031] Attention is now directed to FIGS. 2-4B, 7 and 8 where a methodand apparatus are illustrated for increasing the rate of proliferativecell growth and/or induce thrombus formation for a selected region 21 ofcellular tissue 22. Briefly, the method includes the step ofendovascularly irradiation the selected region with radiation, having adose range of endovascular radiation of about 1 Gy to about 600 Gy at alow dose rate of about 1 cGy/hr to about 320 cGy/hr, for increasing therate of cell proliferation and/or induce thrombus formation of theaffected selected region. An endovascular device, generally designated23, is adapted for endovascular positioning in close proximity to theselected region 21 of cellular tissue 22. The endovascular deviceincludes a radioactive material or source collectively delivering aradioactive field upon the selected region 21 of a dosage adapted toincrease the rate of cell proliferation and/or induce thrombus formationin the affected selected region 21.

[0032] While external exposure of living cells or cellular tissue, in asingle or fractionated dose, to a low level radioactive field has beenshown to accelerate proliferative cell growth, Circulation Research,January 1962; X:51-67; Radiotherapy & Oncology 1994; 32:29-36; Int. J.Radiation Oncology Biology Physics, 1987; 13:715-722; JACC April1992:19:5:1106-13, endovascular radiation exposure is advantageous inmany respects. For example, this approach tends to be less invasive thanopen surgery. A longer duration of radiation exposure, moreover, may beachieved at lower radiation levels to provide similar radiation doses,as opposed to the single or fractionated doses of the external methodgenerally at higher relative radiation levels. A continuous irradiationenables a continuous promotion of thrombosis on the vascular surface toestablish a matrix for cellular adhesion, while a constant low doseirradiation provides a continuous stimulation of cellular proliferation.As will be discussed in greater detail below, selectively increasingcell proliferation and/or inducing thrombus formation has enormousmedical device and biotechnological implications. Further, this approachis applicable to a wide range of cellular tissue, such as endothelialcells, myofibroblast cells, fibroblast cells, other fibroblast-typecells, inflammatory cells, smooth muscle cells of different phenotypes,spindle-type cells and other connective tissue.

[0033] In accordance with the present invention and as will be shown inExperiment A described below, by providing a dose of radioactivity inthe range of about 1 Gy to about 600 Gy at about 0.1 mm from the stentsurface, and at a low dose rate of about 1 cGy/hr to about 320 cGy/hr,the rate of proliferative cell growth and/or thrombus formation may beselectively increased. For example, the rate of proliferative cellgrowth secondary to thrombosis (fibrin deposition, platelets adhesion,and erythrocytes and inflammatory cell aggregation) has been observed toincrease by between about 100% and about 500% in a time frame of about 3months as compared to a control non-radioactive implant. Morepreferably, the radioactive dose is in the range of about 1 Gy to about25 Gy at about 0.1 mm from the stent surface, and at a low dose rate ofabout 1 cGy/hr to about 15 cGy/hr.

[0034] To generate a uniform radioactive field, a radioactive materialor source is preferably positioned in close proximity to the selected ortarget region of cellular tissue such that the proper dose ofradioactivity can be applied thereto. This radioactive source ispreferably provided by implantable structures which can be alloyed,embedded, or implanted with the proper radioactivity of radioisotopes sothat the proper dose of endovascular radiation may be endovascularlyemitted to the designated selected region. Such implantable structures,for example, include intraluminal endovascular prosthesis such asstents, stent grafts, or covered stents can be made radioactive toprovide low dose radiation on the luminal surface in promoting fibrindeposition, cellular adhesion, and cellular proliferation on theselected region 21. Other implantable structures include emboli coils 25(as shown in FIGS. 12A and 12B, and to be discussed in greater detailbelow) or the like, which may be irradiated or made radioactive todirect the radiation to target region 44. Still other implantablestructures include radioactive seeds 43 and radiosensitizers (as shownin FIG. 11, and also to be discussed in greater detail below) which maybe deployed to target selected region 21 of the cellular tissue.

[0035] Accordingly, the emission of the proper dose of endovascularradiation, as will be apparent below, requires consideration of factorssuch as the coil or structure density of the implant device, theproximity to the desired selected region, the dose rate, volume of thetarget tissue, specific type of isotopes, and the half-life of theparticular type of radioisotope employed.

[0036] Typically, the emission of the radioactive dose from theimplantable structures will be omnidirectional in nature, and generallyonly affect the cellular tissues in close proximity to structure.Moreover, the radioisotopes employed for the purpose of the presentinvention are preferably alpha, beta or low energy gamma emitters. Otherconsiderations include the predetermined depth of penetration of theradiation to the target region, the vascular and device geometry, aswell as the specific type of isotope, and the half-life of theradioisotope.

[0037] Regarding the specific type of isotope, briefly, different typesof isotopes generate different types of radiation. Phosphorus 32 (³²P),for instance, is a pure beta-particle emitter while Paladium 103 (¹⁰³Pd)is an X-ray photon emitter. Each type of radiation, moreover, generatesdifferent amount of energy which in turn affect the depth ofpenetration, as well as the amount of radiation absorbed by the targetedtissue. Gamma or X-ray photon as a wave, as an example, typicallypenetrate further into the tissue, as compared to alpha particles with amass which penetrate into the tissue the least. Beta particles, on theother hand, typically penetrate into the tissue between the gammaparticles and the alpha particle. Preferably, the device will be usedwith a beta or low energy gamma emitter.

[0038] Concomitantly, the described properties of the isotopes must beemployed to determined the desired amount of radiation which is to beirradiated from the device. For instance, in order to achieve anequivalent dose of about 1470 cGy at about 0.1 mm from the stent surfaceof a 15 mm length stent, a ³²P irradiating stent requires aradioactivity of about 0.93 μCi whereas a ¹⁰³Pd irradiating stentrequires a radioactivity of about 160 μCi.

[0039] As set forth above, another consideration is the desiredhalf-life of the radioisotope particle which preferably ranges fromabout one (1) hour to less than about one (1) year. The half-life of thepreferred optimum emitter may be about one (1) day to less than abouttwelve (12) weeks, and most preferably about two (2) weeks to less thanabout nine (9) weeks. Depending upon the size of the vascular disorder,the depth of the vessel wall, the dose rate, the required energy leveland predetermined half-life may be selected to optimize vascular repair.Radioisotopes such as Phosphorus 32 (³²P), Yttrium 90 (⁹⁰Y), Calcium 45(⁴⁵Ca), Palladium 103 (¹⁰³Pd) and Iodine 125 (¹²⁵I), for example, havebeen found to be particularly beneficial. For instance, Phosphorus 32 isa pure β-particle emitter, and it typically has a maximum energy of 1.69MeV, an average energy of 0.695 MeV, a half-life of 14.3 days and amaximum particle penetration of a about three (3) millimeters intocellular tissue.

[0040] One preferred application for the present invention is for use inthe field of endovascular aneurysm repair, and more specifically, foruse in combination with stent graft or covered stent devices or thelike. As shown in FIG. 2, a blood vessel 22 is illustrated having afusiform aneurysm 21 which is endovascularly excluded from the vessellumen 26 by a radioactive intraluminal endovascular prosthesis 23 (e.g.,a stent graft). This stent graft 23 is constructed to deliver a dose ofendovascular radiation upon the selected region 21 (i.e., the arterialwall of the aneurysmal sac 27 that is formed between the stent graft andthe wall of the blood vessel), while maintaining vessel patency. Whenthe stent graft is properly positioned and placed in the vessel 22, theaneurysmal sac 27 will be endovascularly excluded from fluidcommunication with the blood flow through the vessel lumen 26.

[0041] In accordance with the present invention, exposure of theexcluded organic fluids (primarily blood) contained in the aneurysmalsac 27 to the above-indicated dose of endovascular radiation increasesthe rate of cellular migration and proliferation from the surroundingconnective tissue and vascular wall. Ultimately, cell colonization willbe induced to seal the aneurysmal sac 27 with fibroblasts orspindle-typed cell growth to repair the aneurysm (FIGS. 2, 8 and 10). Inthis configuration, thus, the selected region targeted for irradiationpreferably includes the arterial wall and adventitial tissues such assmooth muscle cells and fibroblats and the blood contents contained inthe excluded aneurysmal sac such as platelets, clotting proteins, andfibrin.

[0042] In the luminal aspect, as viewed in FIG. 9 and excluded in FIGS.2, 8 and 10 for clarity, a similar mechanism is taking place in theimpervious graft lumen 32. Thrombus formation in the graft lumen 32, aspreviously indicated, is difficult to achieve in a short time periodsince there is a lack of promotional factors such as natural thrombosis.Exposure of the interior surface of the graft lumen 32 to this low levelradiation substantially induces thrombus formation (i.e., plateletadhesion and fibrin deposition) therealong which, in turn, commencescascade of endothelialization of the lumen. Briefly, during theThrombotic Phase, the initial response is explosive activation,adhesion, aggregation and platelet deposition. In less than twenty-fourhours, fibrin-rich thrombus accumulates around the platelet site. Next,during the Recruitment Phase, the initial appearance of cellularinfiltration (monocytes and macrophages) occurs, followed by endothelialcells 24. Finally, during the Proliferative Phase, the actin-positivecells colonize the residual thrombus, resorbing the thrombus. SmoothMuscle Cell migration and proliferation into the degenerated thrombuscreates substantially increased neointimal volume.

[0043] Exposure of the blood contents in the gap 27 to this dose ofradiation has been determined to be beneficial in two respects. First,the rate of thrombotic formation in the luminal surface of the graft hasbeen found to substantially increase which ultimately shortens theThrombotic Phase. For example, a dose of endovascular radiation ofbetween about 1 Gy and about 50 Gy has been shown to induce thrombusformation along the interior surface in 28 days or by a rate increasedby 4-20 times (See Experiment A). By inducing thrombosis, which is theinitial step towards endothelization of the lumen interior surface 29,proliferative cellular healing can commence. One hypothesis for theinducement of thrombus formation is due to the inflammatory responsewhich induces the platelets, erythrocytes, and fibrin to adhere to theluminal surface 29 at a faster rate.

[0044] Second, the increased proliferative cell growth shortens both theRecruitment Phase and the Proliferative Phase in both theendothelialization of the lumen interior surface, as well as the repairof the aneurysmal sac 27. One theory for the increase in the rate ofcell proliferation and is that the low level radiation causes a mildstimulation to the cells such as smooth muscle cells, inflammatorycells, and fibroblasts. In response, increased biochemical moleculessuch as cytokines to the region occurs which increases the rate ofvascular repair and further enhances the cascade of healing.

[0045] Referring back to FIGS. 3 and 4B, one technique of deployment ofthe stent graft 23 of the present invention is illustrated. The deliverymay be performed through conventional open surgery or endovascularcut-down techniques. More preferably, the stent-graft delivery isperformed percutaneously using a guide wire (not shown) positionedthrough vessel 22 and conventional stent-graft delivery system 28. Aballoon expandable radioisotope stent graft 23 is provided having adeformable, tubular stent 25 and a thin walled material graft 30coaxially aligned and mounted onto balloon 31 at a distal portion ofstent-graft delivery system 28. FIGS. 3 and 4A illustrate the balloonand mounted stent graft 23 in a contracted condition which enablespercutaneous advancement of the distal portion of the catheter throughthe vessel to the treatment site. Once endovascularly positioned,selective inflation of the balloon 31 radially expands the stent graft23 from the contracted condition (FIG. 4A) to the expanded condition(FIG. 4B). Such exposure secures the stent against and into the intimaof the vessel to prevent migration of the stent, and to promoteanastomoses with the stent. Use of the radiation shields or the like maybe employed to reduce unnecessary exposure to the radioactive fieldduring percutaneous delivery. One such patented radiation shield forradioisotope stents is disclosed in U.S. Patent No. 5,605,530 toFischell et al.

[0046] It will be appreciated that the stent graft 23 is sized anddimensioned such that an upstream portion of the stent graft 23 isadapted for positioning just upstream of the aneurysm 21, while adownstream portion thereof is adapted positioning just downstream of thevascular disorder (e.g., aneurysm 21) each by at least about 1.0 mm.Preferably, these anchor regions of the stent, which may be provided byhooks, sutures or shape memory alloys such as NiTi, typically contactthe intimal surface of the vessel along a sufficient longitudinaldimension to anchor the stent in place. When combined with the tubularsheath device or material graft 30, a blood impervious luminal surface29 of the material graft endovascularly excludes the aneurysm 21 fromthe blood flow lumen to define the aneurysmal sac 27. Moreover, thematerial graft 30 and the expanded stent 25 cooperate to provide graftlumen 32 therethrough to maintain vessel patency.

[0047] Another stent delivery approach for vascular disorders isdelivery through conventional cut-down techniques. Briefly, in this moreinvasive surgical technique, an incision may be made at the aneurysmalsite for direct insertion of the stent graft therein. Upon properdeployment and anchoring of the stent graft, the incised arterial wallis opposed and is sutured together to close the incision, enveloping thegraft within the lumen.

[0048] As set forth above, one problem associated with these prior artstent graft assemblies was the seal formation and seal integrity at theupstream portion of the stent graft with the interior wall of the bloodvessel 22 (i.e., the intima). This seal is important to secure isolationof the aneurysmal sac 27 from the blood vessel lumen 26 which isdesirable to be reproducible and to be performed as quickly as possible.In accordance with the present invention, in the aneurysmal sac aspect,the radioactivity endovascularly emitted from the stent surface directlyupon the target endothelial cells of the intima at the proximal anddistal end portions end 40, 41 of stent graft substantially increasesanastomosed proliferative cell matrix growth thereof at these contactregions. Hence, seal formation between the vessel 22 and the contactingproximal and distal end portions of the stent graft is substantiallyfacilitated by the increase rate of proliferative cell growth. While notillustrated at the end portions of the stent graft in FIGS. 2, 8 and 10for clarity, upon proper accelerated healing in the advancedproliferative stage, the neointimal layer 34 (i.e., the matrix formationwith its cellular constituents) and the new endothelial layer 24 (FIG.9) lining the stent graft lumen 32 grow over the proximal edge 33 andthe distal edge 35 of the material graft 30, and the correspondingproximal and distal edge 36, 37 of the stent 25 to seal the aneurysmalsac 27 from the vessel lumen 26 and the graft lumen 32

[0049] Further, once the aneurysmal sac 27 is endovascularly excluded,thrombosis naturally commences therein which may be further advanced bythe emitted radiation. However, as the radioactivity is endovascularlyemitted from the stent surface in the proper dose and at the proper doserate to the target fluids contained in the excluded aneurysmal sac 27(FIG. 7), the residual blood clotting and inflammatory response induceproliferative cell growth and connective formation. In the advancedstages of healing, as best viewed in FIGS. 8 and 9, an arterial media 39forms the connective tissue growth which eventually binds the vesselwall 26 against the exterior circumferential surface of the stent graft.

[0050] In the luminal aspect, as shown in FIG. 9, the proper dose ofendovascular radiation emitted from the stent 25 will induce thrombusformation on the interior surface 29 of the material graft 30 definingthe lumen. As the platelets and fibrin are induced to adhere to theinterior surface 29 by the emitted radiation, a fibrin rich thrombuslayer with trapped erythrocytes is deposited along the entire length ofthe lumen. This initiation of the localized thrombotic process functionsas the initial building blocks for endothelialization of the stent graftlumen. In the recruitment phase, endothelial cells subsequently appear,followed by intense cellular infiltration. Finally, during theproliferative phase, actin-positive cells colonize the residualthrombus, resorbing the thrombus and forming a thin intima layer ofendothelial cells lining the interior surface. In accordance with thepresent invention, this low dose endovascular radioactive stent grafthas been shown to increase the rate of endothelialization about severaltimes faster than conventional techniques.

[0051] To further facilitate platelet adhesion and thrombus formation,and/or cell proliferation, the interior surface 29 of the material graft30 may include a biomaterial coating of biological growth factor to forma template in which cells may adhere. One such organic substance ispreferably provided FIBRONECTIN® or collagen or the like. Additionally,the use of the present invention device in combination with proteins(e.g., fibroblast growth factors), or gene thereapy (e.g., VEGF) canprovide beneficial results.

[0052] It will be appreciated that the endovascular prosthesis 23 may beprovided by any conventional stent design capable of expansion andretention from a contracted condition to an expanded condition. Forinstance, a tubular slotted stainless steel Palmaz-Schatz stent fromJohnson and Johnson Interventional Systems may be employed with thepresent invention. Another stent pattern, as shown in FIG. 5 which isthe subject of a stent design disclosed in U.S. Pat. No. 5,697,971 toFischell et al. and incorporated by reference herein in its entirety,may also be deployed with the present invention. As mentioned, one ofthe factors determining the amount of irradiation of the stent,necessary to endovascularly irradiate the appropriate dose ofendovascular radiation to the selected region, is the stent design. Forexample, the denser the stent pattern or number of coils, the moreuniform the dose of endovascular radiation. For the stent design ofstent 25 illustrated in FIG. 5, the stent activity is preferably betweenabout 0.07 μCi/mm to about 0.8 μCi/mm to provide a dose of endovascularradiation in the range of about 1 Gy to about 600 Gy from about 0.1 mmof the stent surface where the selected region 21 is preferably about1.0 mm to about 3.0 mm from the surface of the stent. More preferably,the stent activity is between about 0.13 μCi/mm to about 0.2 μCi/mm.

[0053] This dose distribution is better illustrated in FIG. 6 whichrepresents a two-dimensional graph of the Dose to Tissue vs. DistanceFrom the Surface of the Stent. In this configuration, the radioactivefield becomes relatively more uniform as little as 0.5 mm from the stentsurface which endovascularly irradiates a dose of about 10,000 cGy; andsubstantially more uniform from about 1-3 mm away from the stentsurface. This graph represents measurements taken from stent designsubstantially similar to that of the '971 patent irradiated withphosphorus 32 (³²P) isotope with an activity of about 1.33 μCi/mm with a3 month total dose.

[0054] In the preferred embodiment, the material graft 30 is provided bya relatively flexible material composition which enables expansion fromthe contracted condition to the expanded condition and is impervious toblood flow. Such materials may include DACRON®, TEFLON®, PET(Polyethylene Terephthalate), polyester or a biocompatible metallic meshmaterial. This material graft 30 is affixed to the stent 25 usingconventional anchor means employed in the field to prevent migrationthereof along the stent. Further, as best viewed in FIGS. 3-4B, theproximal edge 33 and the distal edge 35 of the material graft 30preferably terminate at or at a position slightly less than thecorresponding proximal and distal edge 36, 37 of the stent 25. Thisconfiguration prevents any overhang of the ends of the material graftinto either of the openings of the stent to minimize any current orpotential occlusion of the stent passageway. This is especiallyproblematic should excess in-growth be experienced at the ends of thestent graft were formation of the seal is to occur.

[0055] Once the stent graft 23 is properly positioned and moved to theexpanded condition so that the aneurysmal sac is occluded from the lumen26, the radioactive stent 25 of the present invention will beginendovascularly irradiating or delivering radioisotopes to the materialscontained in the sac in the proper dose of endovascular radiation (FIG.7). As mentioned above and in accordance with the present invention, thethrombotic phase is accelerated by the radioactivity, as is therecruitment phase and the proliferative phase for endothelialization ofthe aneurysmal sac 27 for aneurysm repair (FIG. 8).

[0056] In an alternative embodiment, the stent graft may be configuredto irradiate different levels of radiation longitudinally and/orcircumferentially along the stent. For example, in a peripheral aneurysmwhere the dilation is not circumscribed, full circumferential healingmay not be necessary along the vessel wall. Hence, the endovascularirradiation from the stent may not need to be uniformly applied, aswell. In another example, a stent graft having an uniform radioactivitylongitudinally therealong will not emit a uniform dose rate of radiationnear the proximal and distal ends there, as compared to the center ofthe stent graft, due to the distribution geometry. Accordingly, it maybe desirable to selectively apply the desired amount of radioactivityalong the geometry to either increase or inhibit cellular proliferation.

[0057] Moreover, to limit potentially occlusive in-growth at theproximal and distal ends of stent graft 23, the proximal and distal endportions of the stent which anchor the stent to the vessel may havedifferent activities as compared to the growth inducing radioactivity ofthe central portion 38 of the stent (FIG. 8). The proximal and distalend portions 40, 41 of the stent graft 23 which physically contact theendothelial cells of the intima may be embedded or irradiated with anactivity which reduces proliferative cell growth. However, it will beappreciated that the reduction of cell growth should not be at amagnitude where sealing time and reproducibility are detrimentallyaffected, or where seal integrity formation at the end portions iscompromised.

[0058] Such secondary stent activities and resulting doses ofendovascular radiation are disclosed in U.S. Pat. Nos. 5,176,617 and5,059,166 to Fischell et al., incorporated herein by reference.Preferably, the secondary activities are positioned on opposed sides ofthe central portion 38 and extending beyond the upstream end and thedownstream end of the aneurysm.

[0059] Another approach to limit occlusive in-growth at the proximal anddistal end portions of the stent graft would be to subsequently exposethose portions to higher levels of radiation which decrease cellproliferation. For example, after the radioactive stent graft of thepresent invention has been deployed and the proximal and distal endportions have been sufficiently anastomosed to seal and endovascularlyexclude the aneurysmal sac from the vessel and graft lumen, the endportions may be irradiated with radioactive isotopes at levelssufficient to decrease or prevent further cell proliferation. It will beappreciated, however, that such radiation dosages should not be so highas to damage the target tissue at the proximal and distal end portions.

[0060] Delivery of such radiation may be performed endovascularlythrough catheters or the like, or may be performed through more externaltechniques such as external beam irradiation.

[0061] This technique may also be applied to smaller branch vesselswhich are to be anastomotized to the side of stent graft (not shown). Inthese configuration, embodiment, after the vessel has sufficientanastomosed to the stent graft, the immediate area surroundinganastomosis site may be irradiated with the above mentioned higher levelof radiation to decrease or prevent further cell proliferation.

[0062] In another alternative embodiment, the tubular material graft 30may be positioned along the exterior surface of the stent 25, as shownin FIGS. 10 and 11. This covered stent also provides an imperviousluminal surface 42 which prevents fluid communication between thestent-graft lumen 32 and the aneurysmal sac 27 so that thrombusformation and cell growth may be accelerated with the proper dose ofradioactivity.

[0063] In yet another alternative embodiment, radioactive seeds 43 maybeimplanted into the excluded aneurysmal sac 27 in combination with eithera stent graft or covered stent. This radioactive seeding may be employedalone with a non-radioactive stent 25, or together with a radioactivestent. As shown in FIG. 11, the cumulative affect of the radioactiveseeds produce the preferred dose of radioactivity to increase thecell/thrombus proliferation. In the preferred form, these particles 43may be provided by stainless steel or platinum seeds about 0.1 mm toabout 2 mm in diameter, and embedded with the proper activity ofradioisotopes. Depending upon the desired density distribution of theimplanted seeds in the aneurysmal sac 27, the activity of the seeds canbe determined to produce the cumulative dose of endovascular radiationto be delivered to the selected region 21. In the preferred form, thedensity of the distribution of radioactive seeds is about 2particles/cm³, while the activity per seed is about 0.1 μCi to about 0.5μCi.

[0064] Once the stent graft or covered stent 23 is properly deployed orpartially deployed, the radioactive seeds 43 may be deposited into theoccluded aneurysmal sac 27 to induce thrombus formation and accelerateproliferative cell growth. Preferably, the seeds are implanted throughconventional injection techniques, through lumens of a (seed) deliverycatheter or placement during open surgery.

[0065] In still yet another embodiment, the graft may be embedded with aradiosensitizer capable of being activated by either an external orendovascular radiation source. Once activated, the radioactive stentwould subsequently emit the proper dose of radiation to increase therate cell proliferation and/or induce thrombosis. Another approach wouldbe to deliver or seed the aneurysmal sac 27 with a radiosensitizer,similar to the radioactive seeds, and then activate the same to emit theproper dose of radiation. One such radiosensitizer, for example, mayinclude halogenated pyrimidines, while the activator may be provided byan X-ray, ultraviolet, and external electron beam source.

[0066] Turning now to FIGS. 12A and 12B, a saccular or pseudoaneurysm21, such as an intracranial aneurysm, is illustrated which is formedalong an upper portion of vessel 22. In accordance with this embodimentof the present invention, a radioactive coil emboli 25 may be implantedand anchored in the aneurysmal sac 44 of the pseudoaneurysm 21 to induceintravascular thrombosis (FIG. 12A). By irradiating or embedding thesetypically stainless steel or platinum coils with radioactivity, thrombusformation can be accelerated when the coils 25 deliver endovascularradiation of the proper radioactive dose to the aneurysmal sac 44 of thepeusdoaneurysm 21. Once the thrombus phase is complete, the rate of therecruitment phase and the proliferative phase are also increased by theradioactivity emanating from the coil. As shown in FIG. 12B, thepseudoaneurysm 21 will then be repaired once the cell growth fill in theaneurysmal sac 44 of the pseudoaneurysm 21.

[0067] Similar to the radioactive seeds, the activity of the coilsdepends upon the predetermined coil density when positioned in theaneurysmal sac 44 of the pseudoaneurysm. Of course, a higher coildensity to increase thrombogenicityic will require a smaller activity togenerate a uniform radioactive field in the desirable range of about 1cGy to about 600 cGy.

[0068] Still other embodiments may include a radioactive external beamdevice (not shown) which may be positioned on the outside of the vesseland disposed adjacent to the aneurysm sac or gap. This device may beused in combination with a radioactive or non-radioactive stent graftdevice to promote the rate of vascular repair of the vessel. In thisconfiguration, the beam may be configured to focus the endovascularradiation toward the aneurysmal sac.

[0069] In still other combinations, the radioactive coil emboli may beemployed in the aneurysmal sac in combination with a radioactive ornon-radioactive stent graft (not shown). In this manner, the coil emboliwill function in the same manner as the radioactive seeds.

[0070] A radioactive catheter wire (not shown) may be advancedpercutaneously through the vessel and into the aneurysm to promote andaccelerate thrombosis and vascular repair. This temporary radioactivewire may then be removed upon completion of the proper dose ofendovascular radiation. This configuration may also be applied incombination with radioactive or non-radioactive stents, stent grafts,covered stents, coil emboli or the seed embodiments above-mentioned.

[0071] As mentioned above and in accordance with the present invention,the radioactive stent, coil emboli or seed embodiments may apply anyother cellular growth inducing materials which are utilized to promotecellular growth. For example the exterior stent surface or the exteriormaterial graft surface, as well as the graft interior surface, may becoated with a conventional tissue growth inducing biomaterial such asFIBRONECTIN®, VEGF or the like.

[0072] Other medical application upon which the present invention mayapply include the rate of increase of cell growth proliferation ofvascular dissections, wound healing, wound closures, atrial septaldefects, atrial venus malformation, orthopedic implants to encourageosteoblast growth with the use of bone chip gel with radiation, andvaricose veins, to encourage cell proliferation in obliteration of thelumen.

[0073] The following Experiment A serve to more fully under theabove-described invention, as well as to set forth the best modecontemplated for carrying out various aspects of the invention. It is tobe understood that this example in no way serves to limit the true scopeof the invention, but rather are presented for illustrative purposes.

EXPERIMENT A

[0074] Overview: A radioactive stent in accordance with the presentinvention was placed within the artery and the vascular response to theirradiation was examined at different time points after the stentplacement. The endovascular irradiation (brachytherapy) was observedusing the IsoStent BX™ radioactive stents. The isotopes were Phosphorus32 (³²P) and Yttrium 90 (⁹⁰Y). Briefly, ³²P is a pure beta-emittingparticles with a half-life of 14.3 days, an average energy of 0.60 MeV,and a maximum energy of 1.7 MeV. The ⁹⁰Y is also a pure beta-emittingparticles with a half-life of 2.7 days, an average energy of 0.90 MeV,and a maximum energy of 2.3 MeV. These radioactive stents were implantedin the coronary arteries of forty Yucatan miniature pigs, and thevascular response was analyzed for three (3) months after theimplantation.

[0075] Stent Preparation: Proprietary stent of 15 mm length, tubularstainless steel IsoStent BX™ stents were made radioactive by either thedirect ion implantation method or the radiochemical method. In the studywith ³²P, this radioisotope was directly ion implanted beneath thesurface of the metal (Forschungszentrum Karlsruhe, Karlsruhe, Germany)to yield an activity level of 0.1, 1.0, 1.5, 3.0, 6.0, and 12.0 μCi atstent implantation into the animals. Such activity levels yielded atotal 3 month dose of ³²P in the range from 1.0 Gy to 600 Gy at 0.10 mmfrom the surface of the stents. The corresponding initial maximumdose-rate at 0.10 mm from the stent surface ranged from 1 cGy/hr to 120cGy/hr. In the study with ⁹⁰Y, the radioisotope was radiochemicallycoated onto the stent surface to yield an activity level of 1.0, 2.0,4.0, 8.0, 16.0, and 32.0 μCi. The total 3 month dose ranged from 3 Gy to280 Gy at 0.10 mm from the stents surface, and the corresponding initialmaximum dose-rate ranged from 5 cGy/hr to 320 cGy/hr. The control samplestents in this study were the non-radioactive BX™-stents of 15 mm inlength and were fabricated in a manner similar to the radioactive stentsexcept for ion implantation of ³²P or radiochemical process. All thesestents were pre-mounted on PAS balloon catheters (Fischell IsoStent™with delivery system, Johnson & Johnson Delivery System).

[0076] The stent radioactivity was determined as follows: In the ³²Pstents, the activity level of each stent was determined by comparison tostandard ³²P sources of known activity using liquid scintillationcounting methods. After ion implantation, the stents were placed in asealed cylindrical acrylic resin radiation shield and gamma-raysterilized in a conventional manner. The stents were then implanted whenthe radiation level had decreased to the desired activity. The radiationlevels at implantation were determined by calculations that used theknown half-life for ³²P (14.3 days) and the following standard“activity” equation: A_(t)=A₀e^(−kt), where A_(t) is the activity levelat the time (μCi), A₀ is the initial activity level (μCi), t is time indays, and k is the rate constant.

[0077] Animal Model: In the ³²P study, 40 Yucatan miniature swineunderwent placement of 70 stents (50 radioactive ³²P (β-particle) BXstents, and 20 control, non-radioactive BX stents) in the left anteriordescending, left circumflex or right coronary artery. In the ⁹⁰Y study,there were 72 radioactive BX ⁹⁰Y stents and 28 control, non-radioactivestents that were implanted in the coronary arteries of 40 Yucatanminiature swine. Animals were medicated with aspirin 650 mg, nifedipineextended release 30 mg and ticlopidine 250 mg by mouth the evening priorto stent placement. Under general anesthesia, an 8F sheath was placedretrograde in the right carotid artery, and heparin (150 U/kg) wasadministered intra-arterial to achieve an activated clotting timegreater than 300 seconds (Hemochron, International Technidyne, Edison,N.J.). After completion of baseline angiography, the 15 mm stents wereimplanted using the guiding catheter as a reference in order to obtain a1:1.2-1.3 stent to artery ratio (i.e., 20%-30% oversizing) as comparedwith the baseline vessel diameter. Stents were manually crimped ontonon-compliant 3.0 or 3.5 mm diameter 10 mm length angioplasty balloons(SCIMED, Maple Grove, Minn.). Placement of the stent was completed withtwo balloon inflation at 12 or 14 ATM for 30 seconds. Angiography wascompleted after stent implant to confirm patency of the stent andside-branches as well as to assess for migration or intra-luminalfilling defects. The animals were allowed to recover and returned tocare facilities where they received a normal diet and aspirin 81 mgdaily. The animals were returned for coronary angiography and euthanasia3 months after the stent implantation. Immediately following theangiography, the animals were euthanized with a lethal dose ofbarbiturate. The hearts were harvested and the coronary arteries wereperfusion-fixed with 10% neutral buffered formalin at 60-80 mmHg for 30minutes via the aortic stump.

[0078] Histology: Non-contrast postmortem radiography was completed oneach stented vessel prior to sectioning in order to assess stentexpansion and structural integrity. The fixed hearts were X-rayed andthe stented coronary artery segments were carefully dissected from theepicardial surface of the heart. Control sections of the adjoiningnon-stented artery were taken from the proximal and the distal ends. Thestented arteries were then processed in graded series of alcohol andxylene and embedded in methyl methacrylate. The plastic embedded stentsare then cut with a rotatory diamond edged blade into 6.0-8.0 mm blocksfrom the proximal, mid, and distal segments of the stent and thensectioned with a stainless steel carbide knife into 4-5 μm sections.Arterial sections proximal and distal to the stent were processed inparaffin and sectioned as above. All histologic section were stainedwith hematoxylin-eosin and Movat pentachrome stains. All three sectionswere examined by light microscopy and used for morphometricmeasurements. The paraffin embedded sections were similarly cut andstained in a routine manner and examined for any abnormalities.

[0079] Statistical Analysis: The mean injury score, neointimal area andpercent area stenosis were determined. Data are expressed as themean±the Standard Deviation (SD). Lesion morphology and injury scorewere compared for the control and radioactive stents using ANOVA with apost hoc analysis for multiple comparisons. The stent activity,neointimal, and medial cell density were analyzed with a polynomialregression model to derive a slope, intercept and correlationcoefficient to determine relations. Significance was established with ap value SD. Lesion morphology and injury score were compared for thecontrol and radioactive stents using ANOVA with a post hoc analysis formultiple comparisons. The stent activity, neointimal, and medial celldensity were analyzed with a polynomial regression model to derive aslope, intercept and correlation coefficient to determine relations.Significance was established with a p value<0.05. All statistics werecalculated using Starview 4.5 (Abacus, Berkeley, Calif.).

Results

[0080] Procedural and postoperative: One animal died due to balloonrupture during implantation of a control stent resulting in severecoronary spasm and refractory ventricular arrhythmias. Ventriculartachycardia and fibrillation occurred in one additional animal whichrequired DC cardioversion to restore a normal sinus rhythm. All animalshad a normal postoperative recovery and resumed a normal pig chow diet(Purina) the following morning after stent implant. There were no casesof wound infection, incomplete healing or dehiscence. Daily observationof the animals indicated normal behavior and dietary intake. All animalshad a stable or mild increase in body weight during the study (baseline29.2+5.1 kg versus 31.2+ 5.5 kg at following-up, p<0.001).

[0081] Blood samples were obtained for complete blood counts in allanimals prior to and at 28 days after stent placement. The mean whiteblood cell count was similar at stent implant and on follow-up study(baseline 12.5+3.0×10³ cells/mm³ versus follow-up 12.6+4.8×10³cells/mm³, p=0.97). The mean hemoglobin concentration was normalbaseline (10.5+1.5 g/dl) and was not significantly different 28 daysafter stent placement (10.3+1.2 g/dl, p=0.72). The baseline (mean429+137×10³ cells/mm³) and follow-up mean (mean 493+110×10³ cells/mm³)platelet count were in a normal range for all animals.

[0082] Follow-up Angiography: Angiography was completed at 3 monthsafter stent placement. Two animals did not have angiographic studybecause of the procedural or post operative complications previouslydescribed. In the 33 animals with 28 day angiographic follow-up,sixty-six of 66 stents (100%) were patent with normal angiographiccoronary flow. There were no cases of stent migration or side-branchocclusion. Quantitative analysis of the coronary angiograms was notecompleted for this study.

[0083] Necropsy: The gross appearance of the mediastinum, pericardiumand myocardium was normal in all animals. The pericardial fluid wasclear and straw colored in all cases. There were no cases with bloody orpurulent pericardial fluid. The epicardial surface of the heart andstented arterial segments when visible were normal in all cases.

[0084] Histology: The radioactive groups for P³² and Y⁹⁰ showed aluminal surface with a complete re-endothelialization. The neointima ofthe radioactive groups had a substantially higher neointimal area andthickness compared to the non-radioactive stents, consisting of smoothmuscle proliferation and matrix formation. A few inflammatory cells werefound on the luminal surface as well as the neointima. The adventitialshowed occasional fibrosis.

[0085] In comparing the ³²P to ⁹⁰Y groups, the ⁹⁰Y groups revealed amore complete re-endothelialization and healing. This may due to theshorter half-life of ⁹⁰Y, which is 2.7 days as compared to 14.3 days.

[0086] The following vascular response parameters were determined:percent luminal reduction, percent adventitial change, presence ofthrombus, percent internal elastic lamina disruption, percent externalelastic lamina disruption, percent medial disruption, and percent ofinflammation.

[0087] The following morphometric measurements were taken: externalelastic lamina area, internal elastic lamina area, stented lumen area,medial area, thrombus area, intimal thickness and area, percentstenosis, and injury score. TABLE 1 Morphometric measurements of ³²Pradioactive stent study neo- neo-intimal μCi/15 m EEL area, IEL area,Lumen Medial intimal thickness, m stent mm² mm² area, mm² area, mm²area, mm² mm2 % stenosis 0 8.34 ± 1.63 6.54 ± 1.12 3.48 ± 1.06 1.81 ±1.06 3.06 ± 1.58 0.41 ± 0.26 45.1 ± 18.1 0.1 7.32 ± 0.98 5.73 ± 0.843.90 ± 0.84 1.59 ± 0.28 1.82 ± 1.10 0.22 ± 0.18 30.7 ± 16.2 0.5 7.21 ±0.97 5.97 ± 0.89 4.06 ± 1.04 1.25 ± 0.55 1.91 ± 1.07 0.22 ± 0.15 31.5 ±15.5 1 7.17 ± 1.39 6.08 ± 1.05 1.89 ± 0.42 1.09 ± 0.39 4.19 ± 0.80 0.68± 0.81 68.7 ± 4.9  1.5 5.90 ± 1.02 4.85 ± 0.73 1.92 ± 0.91 1.05 ± 0.323.93 ± 0.72 0.48 ± 0.18 60.9 ± 15.3 3 7.73 ± 0.75 6.46 ± 0.62 1.82 ±1.07 1.26 ± 0.18 4.64 ± 1.25 0.66 ± 0.13 71.4 ± 17.1 6 7.25 ± 2.16 6.17± 1.65 0.57 ± 0.53 1.09 ± 0.51 5.60 ± 2.12 0.81 ± 0.04 89.3 ± 9.80 128.38 ± 1.77 6.37 ± 1.24 2.14 ± 1.46 2.01 ± 1.01 4.22 ± 1.56 0.64 ± 0.3466.6 ± 21.2

[0088] TABLE 2 Morphometric measurements of ⁹⁰Y radioactive stent study.neo-intimal μCi/15 m EEL area, IEL area, Lumen Medial neo-intimalthickness, m stent mm² mm² area, mm² area, mm² area, mm² mm² % stenosis0 8.55 ± 0.92 6.80 ± 0.77 4.07 ± 1.22 1.75 ± 0.33 2.34 ± 0.98 0.28 ±0.20 40.0 ± 17.2 2 8.32 ± 1.02 6.71 ± 0.88 1.92 ± 0.91 1.61 ± 0.41 2.23± 1.25 0.27 ± 0.22 33.5 ± 18.1 4 8.43 ± 1.44 7.01 ± 1.17 1.82 ± 1.071.43 ± 0.33 2.15 ± 0.66 0.24 ± 0.10 31.1 ± 10.9 8 7.71 ± 1.21 6.24 ±1.13 2.60 ± 1.01 1.47 ± 0.26 3.64 ± 1.26 0.54 ± 0.23 57.7 ± 15.5 16 8.22± 1.26 6.61 ± 1.29 2.50 ± 1.18 1.60 ± 0.83 4.11 ± 1.38 0.61 ± 0.20 61.6± 18.6 32 7.13 ± 1.27 5.97 ± 1.13 2.14 ± 1.46 1.16 ± 0.26 4.07 ± 1.680.57 ± 0.28 67.6 ± 22.7

[0089] For both ³²P and ⁹⁰Y studies, the radioactive stents showed are-endothelialized lumen. The neo-intima showed a dose dependenceincrease of cellular proliferation and cell matrix formation. Thesefindings were evidenced by the increase of neointimal area and thicknessas a function of increased irradiation as compared to the controls. Themedial layer beneath the struts was thinned. The adventitial showed adose dependence increased in fibrosis.

Discussion

[0090] The effects of radiation on vascular cellular proliferation havebeen extensively studied. Lindsay et al applied X-ray radiation on theexposed dog aorta (Circulation Research, volume X, January 1962, page:51-60). The animals were sacrificed at different time points, rangingfrom 2 to 48 weeks following irradiation. The results showed that therewas an accentuation of fibrocellular proliferation at a single dose of 8Gy to 15 Gy and 30 Gy to 55 Gy. The latter group showed less vascularproliferation than the former. The range of the estimated dose-rate wasfrom 176 cGy at the dorsal wall to 320 cGy at the surface of the ventralwall. The fibrocellular proliferation increased with time after theirradiation. The histopathologic findings showed intimal thickening withfibroblastic-like proliferation and some matrix formation. There wasfibrosis of medial and adventitia in response to irradiation. Similarfibroblastic proliferation was observed when the aorta of the dogs wereexposed to a single dose of external electron irradiation of 10-95 Gy(Circulation Research, volume X, January 1962, page: 61-67).

[0091] Other studies examined the vascular response when the radiationdose was fractionated. The results showed similar increased in cellularproliferation. In one study, the rat aorta was exposed to X-rayirradiation of 47 Gy with fractionation of 5.2 Gy (Radiotherapy &Oncology 32, 1994, page 29-36). There was an increased in fibrogeniccytokines and inflammatory cells that led to cellular proliferation,resulting in increased fibrosis. In another study with the aorta of thedogs, using 22-86 Gy in fractionation, there was a marked increased inintimal and medial proliferation (Int. J. Radiation Oncology BiologyPhysics, volume 13, page 715-722). The adventitial and perivasculartissue showed increased fibroblastic response. The 22-38 Gy group showed4 fold and the 60-80 Gy showed about 20 fold increased in intimalthickness as compared to the control group.

[0092] Similar vascular response to external beam irradiation was alsoobserved in the coronary arteries. Schwartz et al exposed the coronaryarteries of the pigs to a single dose of x-ray radiation of 4 Gy to 8 Gyin one day (JACC Volume 19, No. 5, April 1992:1106-13). The resultsshowed a 20% to 50% increase of neointimal proliferation as compared tothe control group.

[0093] The current experiments, applying endovascular radiation to pigcoronary arteries, showed similar results. These studies involved theuse of beta-emitting radioactive stents for endovascular delivery ofradiation. As shown in Table 1 and Table 2, a significant neointimalproliferative response was observed in the ³²P and ⁹⁰Y groups ascompared to the non-radioactive group. More importantly, all theradioactive and the non-radioactive groups showed no bio-compatibilityrelated problems. There was no evidence of foreign body giant cellreaction or excessive inflammatory response. The histologic sectionsshowed no evidence of radiation injury such as necrosis of the arterialwall or the matrix, and the adventitia and the arterial wall revealed noevidence of significant inflammatory reaction.

[0094] The presence of trapped erythrocytes and fibrin material withinthe neointima indicates that radiation induces thrombosis on the luminalsurface. The histopathologic results showed an increase of 100% to 500%of cellular proliferation, which indicates that the radiation promotescellular growth. Although the 0.1 and 0.5 μCi of the ³²P groups showed alesser neointimal thickness and a lower precent restenosis as comparedto the control group, the results suggested a faster and a more completere-endothelialization of the luminal surface. It is believed that thelower amount of irradiation on the surface may stimulate and activatethe proliferation of the endothelial cells.

[0095] The results indicate that the dose for inducing localizedthrombosis and cellular proliferation is 1 Gy to 600 Gy for ³²P and 3 Gyto 280 Gy for ⁹⁰Y. However, it is believed that the total dose that willresult in cellular proliferation range from 1 Gy to 600 Gy, regardlessof the isotopes used. This is the case because the principle ofradiobiology has shown a given cellular tissue will yield the same orsimilar results if given the same dose of radiation regardless of theisotope (i.e beta-emitting or gamma-emitting isotopes) or the method ofdelivery (i.e endovascular or external beam radiation, single dose orfractionation). The corresponding dose rate for inducing cellularproliferation also follows the same principle; that is, the initial doserate of 1 cGy/hr to 320 cGy/hr will promote cellular proliferationregardless of the isotopes used or the methods of irradiation. As forthe amount of activity on the stent, the total activity to achieve thedesired cellular proliferation (in μCi) will vary, depending on theisotope used and volume of target tissue. For example, to achieve atotal dose of 1470 cGy on the surface of the stent, the ³²P stent willrequire to have an activity of 0.93 μCi, and the ¹⁰³Pd stent willrequire an activity of 160 μCi.

[0096] In conclusion, radiation can be used to induce cellularproliferation in the intima, media, and adventitia of the artery. Boththe single dose of radiation and the fractionation of the total dosepromote fibroblastic proliferation. The beta-emitting stents with thestated dose and dose rate showed a pronounced neointimal response andlittle adventitial cellular proliferation. In contrast, the externalbeam irradiation showed cellular proliferation from adventitia tointima. Thus, these radioactive modalities can be used to promotecellular proliferation the selected region of the artery.

What is claimed is:
 1. A method for increasing the rate of at least one of thrombus formation and cell proliferation in a selected region of cellular tissue comprising the step of: endovascularly irradiating the selected region with endovascular radiation to increase the rate of at least one of thrombus formation and cell proliferation of the affected selected region.
 2. The method according to claim 1 wherein, the dose of endovascular radiation is about 1 Gy to about 600 Gy at the graft surface, and at a low dose rate of about 1 cGy/hr to about 320 cGy/hr.
 3. The method according to claim 2 wherein, the dose of endovascular radiation is about 1 Gy to about 25 Gy at the graft surface, and at a low dose rate of about 1 cGy/hr to about 15 cGy/hr.
 4. The method according to claim 1 wherein, said selected region of cellular tissue includes an aneurysm.
 5. The method according to claim 4 wherein, said cellular tissue is provided by a blood vessel and the blood content.
 6. The method according to claim 1 further including the step of: before the endovascularly irradiating step, positioning a deformable endovascular device, adapted to endovascularly irradiate said radiation, in close proximity to said selected region.
 7. The method according to claim 6 wherein, said positioning step is accomplished by deploying the deformable endovascular device adjacent the selected region of the cellular tissue.
 8. The method according to claim 7 further including the step of: before the positioning step, embedding radioactive material in the deformable endovascular device.
 9. The method according to claim 8 wherein, said radioactive material is provided by radioisotopes selected from the group consisting essentially of alpha, beta and gamma isotopes.
 10. The method according to claim 8 wherein, said radioactive material is provided by radioisotopes selected from the group consisting essentially of Phosphorus 32 (³²P) Yttrium 90 (⁹⁰Y), Calcium 45 (⁴⁵Ca), Palladium 103 (¹⁰³Pd) and Iodine 125 (¹²⁵I).
 11. The method according to claim 9 wherein, said radioisotope has a half-life of about one (1) hour to less than about one (1) year.
 12. The method according to claim 11 wherein, said radioisotope has a half-life of about one (1) day to less than about twelve (12) weeks.
 13. The method according to claim 12 wherein, said radioisotope has a half-life of about two (2) weeks to less than about nine (9) weeks.
 14. The method according to claim 6 wherein, said endovascular device further includes an adhesion molecule and a biological growth factor to further induce cell proliferation.
 15. The method according to claim 14 wherein, said the adhesion molecules include FIBRONECTIN®.
 16. The method according to claim 14 wherein, said growth factor includes VEGF.
 17. The method according to claim 1 wherein, said selected region of cellular tissue includes an aneurysm formed in a blood vessel.
 18. The method according to claim 17 further including the step of: before the endovascularly irradiating step, implanting an intraluminal endovascular prosthesis, endovascularly irradiating said radiation, in said vessel proximate said aneurysm.
 19. The method according to claim 18 wherein, said prosthesis is sized and dimensioned to extend beyond an upstream end of said aneurysm and beyond a downstream end of said aneurysm each by at least about 1.0 mm when properly positioned in said vessel.
 20. The method according to claim 19 further including the step of: before the implanting step, embedding radioactive material in the intraluminal endovascular prosthesis.
 21. The method according to claim 20 wherein, said embedding step further includes the step of: embedding a central portion of the endovascular prosthesis, sized to extend substantially adjacent the aneurysm when properly positioned, with a first radioactive activity generating the first named radiation acting upon said aneurysm; and embedding the end portions of said endovascular prosthesis, positioned on opposed sides of said central portion and extending beyond the upstream end and the downstream end of said aneurysm, with a second radioactive activity generating a second radiation endovascularly irradiating a dosage adapted to decrease at least one of thrombus formation and cell proliferation of the affected regions flanking the aneurysm.
 22. The method according to claim 20 wherein, said radioactive material is provided by radioisotopes selected from the group consisting essentially of alpha, beta and gamma isotopes.
 23. The method according to claim 20 wherein, said implanting step includes the step of deploying said intraluminal endovascular prosthesis from a contracted condition to a expanded deployed condition.
 24. The method according to claim 20 wherein, said implanting step includes the step of percutaneously inserting said prosthesis in said vessel.
 25. The method according to claim 19 wherein, said implanting step includes the step of performing an arterial cutdown and inserting said prosthesis in said vessel.
 26. The method according to claim 1 wherein, said endovascularly irradiating step is applied to said selected region for a predetermined amount of time.
 27. The method according to claim 1 wherein, said selected region of cellular tissue includes an aneurysm formed in a blood vessel, and said method further including the step of: before the endovascularly irradiating step, implanting radioactive seeds, generating said radiation, in close proximity to said aneurysm.
 28. The method according to claim 27 further including the steps of: positioning an intraluminal endovascular prosthesis in said vessel in close proximity to said aneurysm; and deploying or partially deploying said endovascular prosthesis from a contracted condition to an expanded condition, wherein said endovascular prosthesis engages the interior walls of said blood vessel in a manner forming a void between the endovascular prosthesis and the aneurysm for receipt of the radioactive seeds therein and such that the radioactive seeds are substantially retained in said void by the endovascular prosthesis.
 29. The method according to claim 1 wherein, said selected region of cellular tissue includes an aneurysm formed in a blood vessel, and said method further including the step of: before the endovascularly irradiating step, implanting radiosensitizer seeds in close proximity to said aneurysm; and activating said radiosensitizer seeds to emit said radiation with an activator.
 30. The method according to claim 29 further including the steps of: positioning an intraluminal endovascular prosthesis in said vessel in close proximity to said aneurysm; and deploying or partially deploying said endovascular prosthesis from a contracted condition to an expanded condition, wherein said endovascular prosthesis engages the interior walls of said blood vessel in a manner forming a void between the endovascular prosthesis and the aneurysm for receipt of the radiosensitizer seeds therein and such that the radiosensitizer seeds are substantially retained in said void by the endovascular prosthesis.
 31. A device for increasing the rate of at least one of thrombus formation and cell proliferation in a selected region of cellular tissue comprising: an endovascular device adapted for endovascular positioning in close proximity to the selected region of cellular tissue, and including a radioactive material collectively endovascularly irradiating the selected region with radiation of a dosage adapted to increase the rate of at least one of cell proliferation, cellular adhesion and thrombus formation of the affected selected region.
 32. The device as defined in claim 31 wherein, said endovascular device is deformable and adapted to position the radioactive material in close proximity to the selected region.
 33. The device as defined in claim 32 wherein, said deformable endovascular device is configured for secured positioning adjacent to an aneurysm in a blood vessel.
 34. The device as defined in claim 31 wherein, said endovascular device is provided by radioactive coils, endovascularly irradiating said radiation, formed for receipt in an aneurysmal sac of a saccular pseudoaneurysm.
 35. The device as defined in claim 31 wherein, said endovascular device is provided by radioactive seeds, endovascularly irradiating said radiation, formed for receipt in an aneurysmal sac of an aneurysm.
 36. The device as defined in claim 31 wherein, said endovascular device is provided by radiosensitizer seeds formed for receipt in an aneurysmal sac of an aneurysm, and formed to endovascularly irradiate said radiation upon activation by an activator.
 37. The device as defined in claim 32 wherein, said deformable structure is provided by a tubular-shaped intraluminal endovascular prosthesis radially expandable from a contracted condition, enabling delivery into said blood vessel, and an expanded condition, radially contacting the interior walls of said blood vessel for implanting thereto.
 38. The device as defined in claim 37 wherein, said endovascular prosthesis is adapted for percutaneous delivery to the selected region in the contracted condition.
 39. The device as defined in claim 37 wherein, said radioactive materials are embedded in said intraluminal endovascular prosthesis.
 40. The device as defined in claim 37 wherein, said endovascular prosthesis further includes a biological growth factor to further induce cell proliferation.
 41. The device as defined in claim 37 wherein, said endovascular prosthesis is configured for secured positioning adjacent to an aneurysm in a blood vessel in a manner such that said prosthesis engages the interior walls of said blood vessel to form a void between the endovascular prosthesis and the aneurysm, and said device further includes; radioactive seeds, endovascularly irradiating said radiation, formed for receipt in said void.
 42. The device as defined in claim 31 wherein, said radioactive material is adapted to endovascularly irradiate a dosage of radiation to the affected selected region in the range of about 1 Gy to about 600 Gy, and at a low dose rate of about 1 cGy/hr to about 320 cGy/hr at about 0.1 mm from the device surface.
 43. The device as defined in claim 42 wherein, the dose of endovascular radiation is about 1 Gy to about 25 Gy, and at a low dose rate of about 1 cGy/hr to about 15 cGy/h at about 0.1 mm from the device surface.
 44. The device as defined in claim 43 wherein,: said radioactive material is provided by radioisotopes selected from the group consisting essentially of alpha, beta and gamma isotopes.
 45. The device as defined in claim 43 wherein, said radioactive material is provided by radioisotopes selected from the group consisting essentially of Phosphorus 32 (³²P), Yttrium 90 (⁹⁰Y), Calcium 45 (⁴⁵Ca), Palladium 103 (¹⁰³Pd) and Iodine 125 (¹²⁵I).
 46. The device as defined in claim 37 further including: a tubular-shaped sheath device defining a lumen therethrough, and cooperating with the endovascular prosthesis to substantially prevent fluid communication between fluid flow through the lumen of the blood vessel and the aneurysm, while maintaining vessel patency.
 47. The device as defined in claim 46 wherein, said sheath device is configured to be positioned along an exterior surface of the endovascular prosthesis substantially from one end thereof to an opposite end thereof.
 48. The device as defined in claim 46 wherein, said sheath device is configured to be positioned along an interior surface of the endovascular prosthesis substantially from one end thereof to an opposite end thereof.
 49. The device as defined in claim 46 wherein, said radioactive material is adapted to endovascularly irradiate a dosage of radiation to the affected selected region in the range of about 1 Gy to about 600 Gy, and at a low dose rate of about 1 cGy/hr to about 320 cGy/hr at about 0.1 mm from the device surface.
 50. The device as defined in claim 49 wherein, the dose of endovascular radiation is about 1 Gy to about 25 Gy, and at a low dose rate of about 1 cGy/hr to about 15 cGy/h at about 0.1 mm from the device surface.
 51. The device as defined in claim 37 wherein, said prosthesis is sized and dimensioned to extend beyond an upstream end of said aneurysm and beyond a downstream end of said aneurysm each by at least about 1.0 mm when properly positioned in said vessel.
 52. The device as defined in claim 46 wherein, the endovascular prosthesis includes a central portion configured to extend substantially adjacent the aneurysm when properly positioned, and having a first radioactive activity generating the first named radiation acting upon said aneurysm; and the endovascular prosthesis including end portions positioned on opposed sides of said central portion and extending beyond the upstream end and the downstream end of said aneurysm, and having a second radioactive activity generating a second radiation having a dosage adapted to decrease at least one of thrombus formation and cell proliferation of the affected regions flanking the aneurysm. 